Peptides face certain limitations as drugs. They lack the ability to enter cells, are inherently unstable within the body, are rapidly broken down into inactive fragments by circulating enzymes, such as proteases, and are quickly filtered from the bloodstream by the kidneys. Stapled peptides seek to resolve those problems. Because many "undruggable" therapeutic targets include those protein–protein interactions in which a-helices are required in lock-and-key-type mechanisms, an approach is to design a-helical peptides that have structural and functional properties that enable them to penetrate into the cell, bind to the therapeutic target, and modulate the biological pathway (1).
Aileron stabilizes peptides by "stapling" them with hydrocarbon bonds into an a-helix. Once constrained in the a-helix structure, the peptides are protected from degradation by proteases. The stabilized a-helical peptides can penetrate cells by energy-dependent active transport and typically have a higher affinity to large protein surfaces (1, 2).
Aileron was cofounded in 2005 by Gregory L. Verdine, chair of Aileron's scientific advisory board, professor of chemistry at Harvard University, director of the Harvard/Dana–Farber Program in Cancer Chemical Biology, and executive director of the Chemical Biology Initiative at the Dana–Farber Cancer Institute. In 2006, Aileron acquired exclusive rights from Harvard University and the Dana–Farber Cancer Institute to develop and commercialize a drug-discovery pipeline of stapled peptides. In 2006–2007, Aileron licensed rights from the fine-chemicals and technology firm Materia for catalysts used in olefin metathesis. Materia holds the rights to the olefin metathesis technology developed by Robert H. Grubbs, professor at the California Institute of Technology, who was awarded the Nobel Prize in Chemistry in 2005 with Richard R. Schrock and Yves Chauvin for their work in olefin metathesis using ruthenium-based catalysts. Part of the reaction scope of olefin metathesis is ring-closing metathesis (RCM), which transforms a diene into a cyclic alkene and is used to create macrocycles, including bioactive cyclic peptidomimetics. Grubbs was one of the first to offer research describing RCM to tether residues of helical peptides (3, 4).